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Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma

Hoa Tang, Mercer University College of Pharmacy

It is estimated that in 2015, there will be more than 73,000 new cases from melanoma diagnoses and about 10,000 deaths caused by melanoma in the United States.1 Checkpoint inhibitors and the mitogen-activated protein kinase (MAPK) pathway inhibitors are suggested to use for patients with advanced melanoma.2 Ipilimumab, which is an anti cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) and nivolumab, which is an anti- programmed cell death 1 (PD-1) monoclonal antibody, are checkpoint inhibitors. A review of combination therapy for treatment of advanced melanoma notes that dual immune-ckeckpoint inhibitors may have potential for improve clinical outcomes due to the distinct mechanism of actions.3

A recently published study compared the combination of nivolumab and ipilimumab with ipilimumab monotherapy in patients with advanced melanoma. 4

Participants were randomized to received ipilimumab ( 3 mg per kilogram) combined with either nivolumab ( 1 mg per kilogram) or placebo once every three weeks for four doses, followed by nivolumab ( 3 mg per kilogram) or placebo every two weeks.

Duration

September 2013 through February 2014; a minimum follow-up of 11 months

Among the patients with BRAF wild-type tumors, the rate of investigator-assessed, confirmed objective response was 61% in the combination group and 11% in ipilimumab monotherapy group ( 95% confidence interval (CI): 3.91-54.49; p<0.001)

Among patients with BRAF V600 mutation positive tumors, the objective response was 52% in the combination group (95% CI: 31-73) and 10% in ipilimumab monotherapy group (95% CI: 0-45)

Percentage that discontinued due to Adverse Events: 47% in combination group and 17% in ipilimumab alone group

Study Author Conclusions

The combination of ipilimumab plus nivolumab resulted in durable responses and a substantially higher objective response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy among patients with BRAF wild-type advanced melanoma and those with BRAF-mutant advanced melanoma. The incidence of grade 3 or 4 adverse events was higher with combination therapy, but adverse events were generally manageable when established safety guidelines were used. The risk–benefit profile of combined PD-1 and CTLA-4 blockade, as compared with monotherapy, will be further clarified by data from ongoing phase 3 double-blind, randomized trials, such as the CheckMate 067 study.

This trial shows that untreated, advanced melanoma patients with BRAF wild-type melanoma had significantly higher response rate to the ipilimumab-nivolumab combination therapy than the ipilimumab alone. As expected, treatment-related adverse events were also much higher with the combination therapy. Although risks versus benefits of dual checkpoint inhibitors combination are still under investigation, this ipilimumab-nivolumab combination may potentially be used for untreated patients with advanced melanoma.